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vitdoc

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As a physician I am constantly reviewing data about new drugs. My practice is involved with a large number of drug studies with a number of very large pharmaceutical companies. So I am aware of efforts made to make the data look the best it possibly can since a lot of money is riding on these trials coming out with a positive outcome. We do the trials in a non biased double blinded approach but the way the data is interpreted can be important. I looked at some of the data on the On-X valve trial. I thought the way the data was presented was interesting.

Interim results are available for the high-risk AVR patients, the only treatment arm that is fully enrolled and closed. In that arm the test group had 185 patients with 247 patient-years of follow-up, and the control group had 190 patients with 257 patient-years of follow-up (patient-years are the number of patients multiplied by their number of years in the study). Results to date suggest that this approach is at least as safe as standard warfarin therapy. Nine patients died: five in the test group and four in the control group. The test group had 2.5 bleeding events/patient-year vs. 4.4/patient-year for the control group, and a stroke rate of 1.3 percent/patient-year vs. 0.4 percent/patient-year for the control group. For the combined endpoint of stroke, clots and bleeding event, rates were 9/patient-year (3.8 percent) for the test group and 12/patient-year (4.9 percent) for the control group. By the time the study ends, 6,000 patient-years of data will be available.

Notice that the stroke rate was 1.3 percent for the test group and the rate was .4 percent for the control group. About 1/3 as many strokes with the higher INR then with the lower INR.
Looks a bit worrisome to me to be in the lower group. However the study developed another parameter to measure the combined endpoint of stroke, clots, and bleeding. This was in favor for the lower INR group. So if this is reported the study is positive or at least non inferior for the lower INR group. But if you looked just at stroke the lower group did not fare as well.
So what kind of bleeding issues were there? What was the severity of the stokes?
Brain bleeds are probably with worst potential bleed types. Bleeding elsewhere is not fun but may not be as severe an issue. So before I would get on the band wagon for the ON-X valve and feel safe to use low INR I would have liked to have seen post study data from the time the valve was released to now. This is often not published or available. Also to really understand if there is a big difference in valves in terms of the ideal INR it would be interesting to have similar studies with other valves such as the St. Jude. This is unlikely to be done. Finally the ON-X studies were also done with low dose aspirin along with Warfarin. What affect not using ASA on these results is unknown. So based on what I have seen keeping the INR around at least 2.5 probably is good policy for everyone with a mechanical valve in the aortic position. Maybe higher for the mitral position. If someone has some specific problem like bleeding GI problems then probably keeping the INR lower would make sense.
 

pellicle

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Hi

...Notice that the stroke rate was 1.3 percent for the test group and the rate was .4 percent for the control group. About 1/3 as many strokes with the higher INR then with the lower INR.
did you mean the other way round?

...So based on what I have seen keeping the INR around at least 2.5 probably is good policy for everyone with a mechanical valve in the aortic position. Maybe higher for the mitral position. If someone has some specific problem like bleeding GI problems then probably keeping the INR lower would make sense.
I would agree with that, however my view on the lower INR experiment was to assuage the troubled souls of those who are "worried" about what warfarin may do ... you know ... like its rat poison right? These people imagine that reducing your dose by as much as 1mg "must be a good thing ... right"

Evidence? TLDR

So On-X tapped into that rich seam of marketing gold...
 

Protimenow

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I found it interesting that they don't have a maximum or minimum of patient years in the study. It's unreasonable to think that none of the patients in either study had only been followed for less than 18 months (the number of patient years divided by the number of patients) but it would have been more enlightening to see rates of events broken into number of patients with five years (and maybe more than 5 years), four years, three years, two years and less than one year after surgery. If, for example, most of the adverse events happened at year five or later, and this is added into the entire group, the results of On-X would look a lot better when distributed over the entire population in the study.
This data, then, doesn't seem to be particularly helpful (to me, at least).

But this is the way that companies (and researchers probably supported by the manufacturers) can fudge data to make it look better than it really is.

I agree - even those with an On-X valve aren't doing themselves any damage keeping their range at 2.5-3.0 or so.
 

vitdoc

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Pellicle I think I was correct in what I said about the stroke rates and the INR.

Nine patients died: five in the test group and four in the control group. The test group had 2.5 bleeding events/patient-year vs. 4.4/patient-year for the control group, and a stroke rate of 1.3 percent/patient-year vs. 0.4 percent/patient-year for the control group



The test group was the lower INR. The control group was the higher INR.
Stroke rate in test group was 1.3%/patient years (lower INR). The control group (higher INR) was .4%/patient years. So the higher INR had a much lower stoke rate.
But the higher INR had a higher bleed rate.
I think another way to look at this is that if you are striving for a low INR (less anticoagulation) if you go too low you run a higher risk of stroke.
If you have a more anticoagulated state i.e a higher INR you run the risk of going the other way had having a very high INR and bleed.
So if the thought of stroke scares you more than bleeding than go with a higher INR. If bleeding worries you more than go with a lower INR.
For me I am scared much more about stroke. I can usually keep my INR fairly stable between 2.5 and 3.0 . With occasional 3.5 or so. And occasional 2.0.
I personally have had at least three episodes of temporary visual loss that passed in one eye from a temporary retinal artery occlusion which fortunately spontaneously improved. But it scared the crap out of me when I went through it. Also again remember the ON-X studies were done with aspirin on board also.
Yes there is a lot of silliness about warfarin. Yes it was a rat poison albeit a poor one. But right now warfarin is the only option for anticoagulation with mechanical heart valves. It also has a 60+ year track record and outside of affecting coagulation has a very good safety profile.
 
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rwsp768

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I have the On-X valve and was kept between 2.0-3.0 for 10 years. In 2016 they lowered my range from 1.5-2.5 14 months later I had a TIA and was told my INR was 1.7 when they got me to ER. The week before was 2.1, now a interesting find was the following day on a MRI they found a clot in the artery running up my spine and part looked as though it had broke off. I had First Responder class every two years for close to 43 years plus years ago was a certified EMT and I never heard of artery's running on either side of the spine much like your carotids and they are so deep that nothing can be done to clean them. Was the low TIA caused by lower INR, I don't believe it was, but again I am no doctor and we all know they are right or so we are told. I am now back to 2.0-3.0.
 

Protimenow

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vitdoc - I'd be interested in what range the control group was in. If it was 2.5 - 5.0 (for example), there would, of course, be more incidence of bleeding episodes. You summarized the conclusions, but I don't think the range defined for 'control' was listed. Can you share the ranges for control and study groups?

Also - I've had that visual thing, too -- it was sometimes accompanied by temporary numbness of one side of the lip or tongue, and temporary numbness in one or more fingers. At the time, I was taking Zyrtec. I personally know of one friend having the same symptoms while on Zyrtec, and there's another person on this forum who has had a similar issue.

It IS scary as hell. Do you recall whether or not you were taking Zyrtec when this episode occurred?

(I took Zyrtec two or three times, and the symptoms recurred. Discontinuing it, and staying the hell away from it, stopped those symptoms from occurring).

I know that this was once a patented, prescription drug. I wonder what the PDR says about adverse reactions to it.
 
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vitdoc

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I am a retinal surgeon. I deal with all sorts of retinal vascular problems. When I had the visual problems I lost half of my visual field in a horizontal fashion. There is nothing that acts like that except for a temporary occlusion of a branch retinal artery. This is often associated with a small embolus probably coming from the heart valve. I have never used Zyrtec.
 

vitdoc

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I don't know the details of the control group. Usually the studies use the term usual and customary treatment. In this case I would guess that means trying to keep the INR in the 2.5 to 3.5 range.
 

Eva

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.... When I had the visual problems I lost half of my visual field in a horizontal fashion. ... I have never used Zyrtec.
I, too, never used Zyrtec and I had a worse visual loss (3/4 of my visual horizontal field) only because my INR was Low!
In my case, though my INR should 2.5-3.5, my surgeon said it’s ok for my range to go up to 4.
 

Agian

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I am a retinal surgeon. I deal with all sorts of retinal vascular problems. When I had the visual problems I lost half of my visual field in a horizontal fashion. There is nothing that acts like that except for a temporary occlusion of a branch retinal artery.
I got that pre surgery and it was discovered I had a PFO. I think the association is becoming more well known. I was straightening up after getting stuff out of the fridge and the lower half of my visual field in the left eye blacked out for a few seconds. It was like a straight line horizontally. I thought the sides were turned up a little.
 

Protimenow

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That visual thing is scary stuff -- especially the first time. When I was taking Zyrtec, I'm not sure if it was the entire field of vision in one eye, or just a portion of the visual field of one eye.

Vitdoc - it's somewhat surprising to see that the study didn't define the INRs of the control group more accurately. It kind of makes me wonder if the control group was above 2.5 - which accounts for more bleeding events, because this may include participants with high INRs. (This would also skew the advantages for On-X users, of keeping the INR low).
 
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